Photodynamic therapy (PDT) is a minimally invasive therapy for the localized treatment of fairly shallow tumors that only requires the presence of a photosensitizer, a light source, and oxygen. The photochemical reaction of light with the photosensitizer results in the formation of reactive oxygen species that induce localized cell killing. Due to spatial control using light application, treatment is limited to a specific area, which can result in fewer systemic effects, greater efficacy, and more cost-effectiveness compared to chemotherapy. However, several significant challenges often limit the practical application of PDT, including poor bioavailability and low accumulation in the tumor tissue, dispersal of the photosensitizer throughout the body necessitating avoidance of sunlight for several weeks following treatment, and the hydrophobic nature of most photosensitizers, making them insoluble in physiological conditions. Agostinis et al., CA Cancer J Clin., 61, 250-281 (2011).
To overcome these challenges, the use of a nanoparticle delivery vehicle for photosensitizers is a potentially advantageous development in PDT due to several benefits, including greater payload delivery that is specific to cancer cells due to both passive and active targeting methods, reduction of toxicity of many hydrophobic photosensitizers that tend to form colloidal aggregates, and prevention of drug inactivation by plasma components. Lucky et al., Chem Rev., 115, 1990-2042 (2015). Plant viruses in particular are useful as delivery vehicles due to their ease of manufacture, monodispersity, biocompatibility, and good safety profile. Manchester M, Singh P., Adv Drug Delivery Rev., 58, 1505-1522 (2006). Viruses have been explored for PDT, with applications shown in the treatment of leukemia T cells (Stephanopoulos et al., ACS Nano., 4, 6014-6020 (2010)), prostate cancer cells (Wen et al., Chem Commun (Cambridge, U K), 48, 9044-9046 (2012)) and CD22+ cells (Rhee et al., Biomacromolecules, 13, 2333-2338 (2012)), as well as for antimicrobial therapy.
As a virus-based delivery vehicle for anticancer applications, the 30-nm-sized icosahedron cowpea mosaic virus (CPMV) is particularly noteworthy as it possesses a natural affinity to cancer cells that results from its specificity for and interaction with surface expressed vimentin. Steinmetz et al., Nanomedicine, 6, 351-364 (2011). Furthermore, it has been demonstrated that CPMV has a preference for immune cells, specifically the M2 subpopulation of macrophages, although the mechanism behind this partitioning has not yet been elucidated. Agrawal A, Manchester M., Biomacromolecules, 13, 3320-3326 (2012). The tumor microenvironment is diverse and consists of more than just cancer cells, and macrophages in particular are a major component as well. Whereas the classical M1 macrophages are involved in immune activation and tumor suppression, there is increasing evidence that tumor-associated macrophages are of an M2 polarization and play a role in the promotion of tumor progression and invasion. Sica et al., Eur J Cancer, 42, 717-727 (2006). The implication of M2 macrophages in suppressing an antitumor immune response makes them a good target for therapy. The elimination of tumor cells together with M2 macrophages has the potential to stimulate the immune system toward destroying any remnant malignant cells. Targeting tumor-associated macrophages in general has resulted in greater nanoparticle accumulation and higher efficacy, allowing them to serve as “drug depots” for delivering drugs such as platinum-based chemotherapies to surrounding cancer cells. Miller et al., Nat Commun., 6, 8692 (2015).
A novel photosensitizing drug that has been developed for bactericidal applications, and only recently explored for its use in cancer therapy (Lee et al., “High-aspect ratio nanotubes formed by tobacco mosaic virus for delivery of photodynamic agents targeting melanoma” ACS Biomater Sci Eng. 2016) is a zinc ethynylphenyl porphyrin (Zn-EpPor) photosensitizer (PS). Porphyrin compounds are commonly applied for PDT (Cui et al., ACS Nano., 9, 4484-4495 (2015)) and the most widely used photosensitizer in the clinic, Photofrin, is composed of porphyrin subunits. PS is unique in that it possesses a positive charge that assists in preferential accumulation in tumor tissue, and its porphyrin ring contains a zinc atom that enhances membrane binding efficiency, both of which makes the photosensitizer more potent.